RGMB enhances the suppressive activity of the monomeric secreted form of CTLA-4
RGMB enhances the suppressive activity of the monomeric secreted form of CTLA-4
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DOI：
10.1038/s41598-019-43068-y
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发表时间：
2019-05-06
影响因子：
4.6
通讯作者：
Takaki, Satoshi
中科院分区：
文献类型：
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作者：
Sekiya, Takashi;Takaki, Satoshi
免疫调节分子CTLA-4在维持免疫稳态中起着至关重要的作用。CTLA-4中和抗体现在被批准用于治疗晚期黑色素瘤，并正在开发中用于治疗其他癌症。然而，有必要在分子水平上彻底了解CTLA-4的功能，以便制定策略来预防意外的自身免疫，这种免疫经常与全身阻断CTLA-4活性有关。在这里，我们描述了一个胞外分子，排斥引导分子B(RGMB)作为CTLA-4的一个新的结合伙伴。在树突状细胞亚群中检测到高水平的RGMB表达，这些亚群被认为具有耐受能力。RGMB结合CTLA-4的胞外区，并特异性地增强单体、可溶性CTLA-4(sCTLA-4)与CD80的结合，增强CTLA-4‘S对共刺激的抑制作用。检测肿瘤组织的表达数据显示，在大多数非血液肿瘤组织中，RGMB的表达与免疫激活状态呈负相关。这些发现促进了我们对CTLA-4活性的理解，并将RGMB/CTLA-4结合界面确定为开发新的免疫检查点阻断疗法的潜在靶点。
The immunoregulatory molecule CTLA-4 plays a crucial role in the maintenance of immune homeostasis. CTLA-4-neutralizing antibodies are now approved for the treatment of advanced melanoma, and are in development for treating other cancers as well. However, a thorough understanding of CTLA-4 function at the molecular level is necessary in order to develop strategies to prevent the unintended autoimmunity that is frequently associated with systemic blockade of CTLA-4 activity. Here, we describe an extracellular molecule, repulsive guidance molecule B (RGMB) as a novel binding partner of CTLA-4. RGMB expression was detected at high levels in dendritic cell subsets that have been suggested to have tolerogenic capabilities. RGMB binds an extracellular domain of CTLA-4, and specifically strengthens the binding of the monomeric, soluble form of CTLA-4 (sCTLA-4) to CD80, enhancing CTLA-4's suppressive effect on co-stimulation. Examination of expression data from tumor tissues revealed a negative correlation between RGMB expression and immune activation status in the majority of non-hematologic tumor tissues. These findings advance our understanding of CTLA-4 activity, as well as identify the RGMB/CTLA-4 binding interface as a potential target for the development of novel immune checkpoint blockade therapies.